Allergic reactions: foods (immediate and delayed galactose-alpha-1,3-galactose), drugs, exercise, venom, contact with allergens (e.g. latex)
Direct mast cell release: opiates, contrast media, muscle relaxants
Aspirin and NSAIDs - possibly leukotriene mediated
Hereditary vibratory angioedema - autosomal dominant (but nonfamilial cases reported), pruritus and swelling within minutes of vibratory stimuli; histamine elevated and antihistamines partially beneficial.

General notes:

Symptoms usually peak in 1-2 hours, resolve in 12-24 (less commonly up to 36) hours, and often associated with pruritus, urticaria, and rarely affect larynx
Angioedema of both lips, or half of them, is a frequent presentation
Often responsive to antihistamines, steroids, epinephrine
Onset at any age

Bradykinin-mediated etiologies

Drug-induced
- ACE inhibitors
  - AE affects 0.1-0.7% of patients treated with ACEI
    - Major risk factors are female, African-American, elderly, and genetically predisposed individuals (polymorphisms in genes involved in bradykinin metabolism)
    - Incidence is increased in patients with allergic rhinitis; patients are more likely to present with ACE-I angioedema during high pollen counts
  - Most commonly ("almost the rule") affects face, lips, tongue; gut rarely involved
  - Usually delayed onset (mean 1.8 years, ranging from 1 month - 10 years, most within first 3 months) and risk of AE may remain increased for 6-12 weeks (possibly more) after discontinuation
- Angiotensin II receptor blockers (ARB)
  - Most patients with AE related to ACE inhibitor usually tolerate ARBs, but there are case reports of AE with ARBs
- Aliskiren (Tekturna) renin inhibitor - angioedema of the face, extremities, lips, tongue, glottis and/or larynx (requiring intubation) have been reported
  - May occur at any time during treatment and in patients with and without a history of ACEI or ARB-induced AE
- Dipeptidyl peptidase-4 (DPP-4) Inhibitors - oral hypoglycemics for DM type 2, e.g. Onglyza, Januvia ("-gliptins")
  - DPP-4 plays a role in bradykinin metabolism, DPP-4 inhibitors reported to increase risk for AE (alone or in combination with ACEI)
- Antiandrogenic drugs (e.g. Dutasteride) may trigger AE by increasing bradykinin levels (antiandrogens result in lower levels of C1INH and increased levels of factor XII) and reducing its degradation (antiandrogens result in lower levels of ACE and aminopeptidase P)
- Estrogens (exogenous from OCPs or endogenous from pregnancy) - may independently cause angioedema (rarely) and promote angioedema in patients with HAE (any type)

Hereditary angioedema
- 25% of HAE with new mutation (negative family history)
- Age of onset may be at any age but usually occurs between 5-11 years old (overall <30 years old)
- Unusual symptoms apart from cutaneous/laryngeal edema:
  - Sometimes preceded by erythema marginatum (macular circular "map-like pattern" rash without pruritus), especially in children
  - Intestinal edema causing colicky abdominal pain, nausea, vomiting, watery post-attack diarrhea, dehydration, and may mimic an "acute abdomen" that can lead to unnecessary surgery
  - May have anosmia/hyposmia
  - 1-2% of attacks can occur in other localizations: urinary bladder, the urethra, muscles and joints, kidney, pericardial or pleural effusions, or neurological symptoms
- Attacks may last 2-5 days, with symptoms typically peaking over 24 h then gradualy resolving over the next 48 h
- Common triggers of types 1 and 2 include mental stress, trauma (surgery), physical exertion, pregnancy, menses, exogenous estrogens, respiratory tract infection, possibly H. pylori infection
- Females can have genital edema; horse riding, bike riding, or sexual intercourse can precipitate genital attacks
- HAE type 3 associated with female predominance, estrogen, normal HAE studies, later age of onset (mean 26.8 years), swelling more likely to involve face and extremities
Acquired angioedema
- New onset in older adults (>40 years), associated with malignancy and autoimmunity

General notes:

Generally have gradual onset (>6 h to peak) and lasts >48 h
Not associated with urticaria
Unresponsive to antihistamines and/or steroids

Etiologies of unknown mechanism

Infection (dental granuloma, sinusitis, UTI, herpesvirus infection found in series of referred patients with AE usually improving after treatment of infection)
Autoimmune disorders (SLE, systemic sclerosis, vasculitis, cryoglobulinemic syndrome, autoimmune thyroiditis found in series of patients referred for AE)
Drugs
- Calcium channel blockers
- Fibrinolytic agents (streptokinase, alteplase)
- Other reported drugs: sirolimus and everolimus, amiodarone, metoprolol, risperidone, paroxetine
- Biologics: Recombinant IL-2, IFN-alpha, etanercept
- Herbal supplements including sanyak, Echballium elaterium, garlic
Other rare causes
- Hypereosinophilic syndrome (HES), Gleich syndrome (episodic angioedema)
- Hypocomplementemic urticarial vasculitis syndrome (HUVS) - may present with angioedema
- Synovial nodules, eosinophilia, rheumatism, dermatitis and swelling (NERDS syndrome) - elevated IgE levels, histology demonstrating necrotizing granulomas, vasculitis, eosinophilis; usually benign course.
- Other diseases found in a large series of patients referred for AE included GERD with H. pylori infection, chronic renal failure, Berger nephropathy, lipodystrophy, CVID
Idiopathic angioedema
- categorized as histaminergic (responds to antihistamines) vs. non-histaminergic
- Often associated with urticaria and positive autologous serum skin test which may be due to autoantibodies to IgE or mast cell FceR1
- ~40% of patients with chronic urticaria also have angioedema

Conditions presenting with symptoms similar to AE

Cutaneous edema
- Contact dermatitis — e.g., facial edema with cosmetics
- Cellulitis and erysipelas
- Facial lymphedema — can be associated with rosacea
- Autoimmune conditions — Edema of the face, periorbital areas, and sometimes the hands can be seen in SLE, polymyositis, dermatomyositis, and Sjogren's syndrome.
- Eyelid edema — Blepharochalasis is an uncommon disorder in which recurrent and episodic eyelid edema leads to atrophic eyelid skin with fine wrinkling and bronze discoloration.
- Parasitic infections — certain parasites can cause periorbital edema that is persistent (e.g. trichinosis and American trypanosomiasis)
- Thyroid — Hypothyroidism can cause myxedema, Graves disease can cause pretibial myxedema
- Superior vena cava syndrome and tumors
- Cheilitis granulomatosa (Miescher's cheilitis) and Melkersson-Rosenthal syndrome — may be associated with inflammatory bowel disease
- Idiopathic systemic capillary-leak syndrome (ISCLS) or Clarkson syndrome — recurrent diffuse subcutaneous edema mainly of the face, hips and hands, with low blood pressure, hemoconcentration, hypoalbuminemia, and often monoclonal gammopathy. ISCLS is a rare acute, lethal condition of recurrent generalized increase in vascular permeability.
- Idiopathic edema — Idiopathic edema is a syndrome of persistent and recurrent fluid retention not related to menstrual cycles, typically occurring in young, menstruating women.
Laryngeal edema — Tonsillitis, peritonsillar abscess, pharyngeal foreign body, uvular edema due to trauma (severe snoring, intubation)
Bowel wall edema — Mesenteric infarction, IBD, acute ileitis (Yersinia, Campylobacter infections), peritoneal carcinomatosis, inflammatory conditions adjacent to the bowel wall.

Evaluation

History

A careful history should include:
- Speed of onset
- Association with urticaria/without urticaria
- Site of AE - facial/peripheral/abdominal pain
- Precipitating factors
- Natural history of attack
- Age of first onset
- Response to treatment
- Drug history
- Family history
- Associated features suggesting rarer syndromes

Basic lab evaluation	Extended lab evaluation (Zingale)	Pediatric lab evaluation (Karagol)
Relevant allergy testing--------- CBC, BMP, LFTs C4 level	Relevant allergy testing CBC, BMP, LFTs, urinalysis C4, C1-INH level and function, C1q Serum protein electrophoresis ESR, CRP Thyroid studies TSH, FT4 Anti-Thyroglobulin, anti-Thyroid Peroxidase Autoimmune ANA RF Autoantibodies to Ro, La, Sm, RNP, Scl-70, Jo, dsDNA-------- Infection Sinus and dental radiographs Stool ova and parasites Urine culture Throat culture	CBC ESR C3, C4 Urinalysis Anti-Thyroglobulin, anti-TPO SPT with a panel of aeroallergens Additional investigations according to history, physical examination and initial tests Urine culture Throat culture SPT or ID/challenges with suspected food or drugs TSH, FT4 C1INH level/function

Final diagnosis of 929 consecutive patients presenting with AE without urticaria (Zingale 2006)
- 41% - Etiology undiscovered (idiopathic)
  - 33% - Idiopathic histaminergic
  - 5% - Idiopathic nonhistaminergic
- 25% - C1-INH deficiency
- 16% - Related to external agents such as a drug, insect bite or foodstuff
- 16% - Lost to follow-up
- 11% - ACE-inhibitor
- 7% - Autoimmune disease or infection
- 3% - Other causes of peripheral or generalized edema (not true angioedema)

Final diagnosis of 95 consecutive pediatrics patients presenting with AE without urticaria (Karagol 2013)
- 51% - Idiopathic
- 21% - Infection-associated
- 14% - Allergic (i.e., related to food, insect bite, latex, or allergic rhinoconjunctivitis)
- 8% - Thyroid autoimmunity-related (i.e., basically euthyroid but thyroid autoantibodies were present, otherwise idiopathic)
- 6% - NSAIDs related

Diagnostic Algorithms

Zingale

Practice Parameter 2013

Treatment

For recurrent idiopathic angioedema, consider daily preventative and/or acute treatment
- Daily preventative treatment
  - Daily high dose antihistamines (e.g. at least cetirizine 10 mg PO BID)
- Acute treatment for attacks, taken at first sign of symptoms:
  - Prednisone 40 mg PO x 1-2 doses
  - Diphenhydramine 25-50 mg PO x 1 or hydroxyzine 50-100 mg PO x 1; consider repeating dose in 4-6 hours
  - Icatibant (bradykinin receptor antagonist) or ecallantide (kallikrein inhibitor) PRN would be theoretically useful in non-histaminergic urticaria
- Consider chronic idiopathic urticaria treatments (cyclosporine, etc.)